Bladder cancer is observed worldwide having been associated with a host of environmental and lifestyle risk factors. Bladder cancer was the fourth most prevalent cancer in men, and fifth overall in 2015. Glucocorticoids (GCs) have been used in bladder cancer for their protective properties against the toxic effects of chemotherapy. GCs may cause resistance to cisplatin, which is a treatment commonly used for bladder cancer. The GC receptor (GR) is expressed as different isoforms, GRα and GRβ, which are a result of alternative splicing of a single gene. GCs bind and activate the ligand-binding GR isoform GRα, which is a transcription factor that increases genes involved in cell cycle arrest and apoptosis. GRβ lacks the ligand-binding domain for GCs, and has been shown to be inhibitory to GRα. A higher total GR expression has been correlated with a better prognosis in bladder cancer. However, the specific roles of GRα or GRβ in bladder cancer are unknown.
Work in the art has yielded a conundrum, in that GCs can suppress bladder cancer invasion but also induce proliferation. GCs are used to inhibit growth in hematological cancers and solid tumors. However, long-term GC treatment can increase the risk of bladder cancer, for uncertain reasons. It has been shown that GRβ can suppress the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and increase Akt1 guided proliferation. Furthermore, GRβ has been shown to be involved in the migratory process of astrocytes and the development of glioblastoma. It has also been shown that the effectiveness of GCs in patients is reduced with a lower GRα/GRβ ratio. Factors that regulate the expression of GRα or GRβ may influence the response to GCs. GC resistance in sepsis has been shown to be affected by microRNA 124 (miR124), which down-regulates GRα, causing increased immune cell growth.
Naturally occurring mutation in the AUUA motif of the 3′ untranslated region (UTR) of GRα and GRβ results in increased mRNA stability and protein expression. Targeting of the 3′ UTR of genes by miRNAs may alter mRNA stability, which is believed to be involved in processes that regulate cancer development or progression. Some miRNAs have been proposed as biomarkers to detect and predict the severity of bladder cancer. The miRNAs that may regulate bladder cancer proliferation may be of importance, which has been shown by miR125b targeting of the E2F3 transcription factor, a tumor suppressor that regulates the cell cycle. Furthermore, miR145 and miR133a decrease bladder cancer aggressiveness by targeting fascin actin-bundling protein 1 (FSCN1), which binds β-catenin to increase motility and invasion. Higher-grade bladder tumors have been shown to express elevated miR144, which has also been shown to promote cell proliferation in nasopharyngeal carcinoma. However, the involvement of miRNAs, and their regulation of GRα or GRβ, in bladder cancer development or progression is unknown.
There is a need in the art for a better understanding of bladder cancer. Moreover, it would be advantageous to develop new therapeutic agents and methods for the treatment, amelioration, or prevention of bladder cancer.